Because of their novel molecular architecture, potent biological activity and fascinating mode of action, the taxane derivatives paclitaxel (I) and docetaxel (II) have become the mainstay in cancer chemotherapy.
R′RPaclitaxel (I)Ac—C(O)—PhDocetaxel (II)H—C(O)—OBu-t
Currently, paclitaxel, which is marketed under the brand name Taxol®, is approved in the U.S. for (i) first-line (in combination with cisplatin) and subsequent therapy for the treatment of advanced carcinoma of the ovary, (ii) the adjuvant treatment of node-positive breast cancer when administered sequentially to standard doxorubicin-containing combination chemotherapy, (iii) the treatment of breast cancer after failure of chemotherapy for metastatic disease or within 6 months of adjuvant chemotherapy, (iv) the first-line treatment of non-small cell lung cancer in patients who are not candidates for potentially curative and/or radiation therapy (in combination with cisplatin) and (v) the second-line treatment of AIDS-related Kaposi's carcinoma.
Docetaxel (Taxotere®) is approved in the U.S. for (i) the treatment of patients with locally advanced or metastatic breast cancer after failure of chemotherapy, (ii) the adjuvant treatment of patients with operable node-positive breast cancer (in combination with doxorubicin and cyclophosphamide), (iii) the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy, (iv) the treatment of patients with unresectable locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy (in combination with cisplatin), (v) the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer (in combination with prednisone), (vi) the treatment of patients with advanced gastric adenocarcinoma, including carcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease (in combination with cisplatin and fluorouracil), and (vii) the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (in combination with cisplatin and fluouracil).
Paclitaxel is found in several species of yew (genus Taxus, family Taxaceae) trees; however, the concentration of this compound is very low. Paclitaxel, docetaxel and their analogues, such as cabazitaxel, are built upon the baccatin III framework. Since the safety and efficacy of paclitaxel and docetaxel are proven, these compounds continue to stimulate synthetic chemists for further refinement of chemical development process. However, these taxane derivatives present a plethora of potential problems related to their synthesis and pharmaceutical compositions containing them, primarily due to stability problems.
Docetaxel is marketed worldwide in its trihydrate form and was first disclosed in U.S. Pat. No. 6,197,980. U.S. Pat. No. 6,022,985 discloses that the trihydrate form has a substantially greater stability than that of the anhydrous form. U.S. Pat. No. 6,022,985 further discloses that trihydrate docetaxel is stable at 4° C., 25° C. and 35° C. in an atmosphere with 90% relative humidity up to 18 months without any danger to its hydrated form whereas the anhydrous form has a tendency to slowly change to the trihydrate form. Further, U.S. Pat. No. 6,022,985 also discloses that it may be advantageous to perform the crystallization in the presence of an acid such as ascorbic acid. However, there is no data in support of any advantageous effect obtained by addition of an acid during crystallization.
Recently, due to the enhanced stability of the trihydrate form of this taxane derivative, there has been an increasing interest in the methods for preparation of taxanes, especially docetaxel in trihydrate form.
U.S. Pat. No. 6,838,569 discloses a process for the preparation of docetaxel and paclitaxel trihydrate using acetonitrile and water. However, again there is no mention of any stability data of docetaxel obtained by such a process. Similarly, U.S. Pat. No. 7,332,617 discloses that docetaxel trihydrate can be prepared by using an acetone/water combination.
It should be noted, however, that the anhydrous as well as the relatively more stable trihydrate form of taxane are liable to undergo degradation, at times drastic, under various manufacturing and storage conditions (for example, temperature, acidic and alkaline media, light, etc.) One of the probable and possibly the most prone pathway for degradation normally observed is epimerization of the hydroxyl group at position 7, which results in formation of the 7-epi-isomer by way of a retro aldol reaction. The epimerization reaction has been observed in alkaline, neutral, and strongly acidic media. Further, in acidic media, or in the presence of electrophilic agents, opening and/or rearrangements of ring D as well as ring B are prominent, whereas in basic media cleavage of the ester groups at positions 2, 4 and/or 13 is observed. It is also reported that 10-deacetyl baccatin III, which is normally employed as a starting material for synthesis of docetaxel, and its epimer (7-epi-10-deacetyl baccatin III) are formed in basic conditions. See, e.g., U.S. Publication No. 2009/0221688, which is hereby incorporated by reference. Basic conditions also lead to formation of 7-epi-10-oxo-10-deacetyl baccatin III. Of these major degradation products of docetaxel, the formation of 7-epi-docetaxel by way of a retro aldol reaction has vexed researchers in this field because 7-epi-docetaxel is thermodynamically more stable and hence its formation is favored. The probable mechanism for formation of 7-epimer of taxane derivative is summarized in Scheme 1.

The degradation of taxane derivatives can result in products with reduced desired pharmacological activity or at times may result in completely inactive products or products with completely different pharmacological and toxicological pattern. Moreover, health authorities all over the world have very stringent requirements for permissible limits of these degradation products in the final formulation.
Hence, there is a need for new synthetic processes which minimize the formation of impurities during the synthesis reaction as well as on storage of taxane derivatives.